PROJECT SUMMARY/ABSTRACT This is an application for a K23 career development award for Dr. Jessica Deleon, a behavioral neurologist who is establishing herself as a junior investigator at the University of California, San Francisco (UCSF). Her long-term goal is to become an independent clinical researcher focused on primary progressive aphasia (PPA) and speech/ language disorders in diverse patient populations. Through the support of this K23 and the optimal, multidisciplinary training environment and resources at UCSF, Dr. Deleon aims to achieve the following training goals: 1) advance her knowledge in multi-modal neuroimaging and the neural basis of PPA; 2) develop skills in study design and biostatistics; 3) gain expertise in neurolinguistics and bilingualism; 4) apply neurogenetics and neuropathology to speech and language networks in PPA; and 5) implement her K23 training and findings into an R01 that focuses on improved diagnosis and treatment of speech/language symptoms in PPA and other language disorders. To achieve these goals, Dr. Deleon has assembled a mentorship team including primary mentor Dr. Maria Luisa Gorno-Tempini, a behavioral neurologist and world leader in PPA and multi-modal neuroimaging; co-mentor Dr. Nina Dronkers, a neuropsychologist and expert in neurolinguistics and bilingualism; Dr. Howard Rosen, a behavioral neurologist focusing on familial frontotemporal dementia and neuroimaging; Dr. Lea Grinberg, a neuropathologist specializing in neurodegenerative disease; Dr. Isabel Elaine Allen, a biostatistician with expertise in study design and statistical analysis; Dr. Manuel Carreiras, a psychologist who has published extensively in bilingualism; and Dr. Pei-Ning Wang, a neurologist with immense knowledge in the evaluation of Mandarin-speaking PPA patients. PPA is a debilitating neurodegenerative disorder that causes progressive loss of speech and language abilities. It can be mis- and underdiagnosed due to heterogeneity in its disease onset and progression, speech/language symptoms and neuroimaging findings. This heterogeneity has significant implications for accurate treatment and clinical trials. In this proposal, Dr. Deleon will investigate how three candidate factors (neuropathology, genetics and spoken languages) influence PPA heterogeneity by developing a comprehensive, multilingual speech/language battery and by utilizing multi-modal neuroimaging techniques (voxel-based morphometry, diffusion tensor imaging and molecular PET imaging). She will apply these methods in a 2-year (3 time-point) cross-sectional and longitudinal study of 530 historical and newly recruited PPA patients. Dr. Deleon will identify speech/language symptoms and neuroimaging signatures that predict underlying neuropathology (Aim 1) and investigate how genetic factors (Aim 2) and language factors (Aim 3) influence PPA heterogeneity through their effects on neural networks. This proposal will provide new knowledge to detect PPA, refine PPA diagnosis and pave the way for improved treatments for individuals with speech and language symptoms related to PPA and related neurodegenerative disorders.